Class II histone deacetylases: Structure, function, and regulation

2001 ◽  
Vol 79 (3) ◽  
pp. 243-252 ◽  
Author(s):  
Nicholas R Bertos ◽  
Audrey H Wang ◽  
Xiang-Jiao Yang
Keyword(s):  
Structure Function ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Dynamic Control ◽  
Class Ii ◽  
Protein Acetylation ◽  
Cellular Processes ◽  
Subcellular Compartmentalization ◽  
Transcriptional Corepressors

Acetylation of histones, as well as non-histone proteins, plays important roles in regulating various cellular processes. Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases (HDACs). In the past few years, distinct classes of HDACs have been identified in mammalian cells. Class I members, such as HDAC1, HDAC2, HDAC3, and HDAC8, are well-known enzymatic transcriptional corepressors homologous to yeast Rpd3. Class II members, including HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9, possess domains similar to the deacetylase domain of yeast Hda1. HDAC4, HDAC5, and HDAC7 function as transcriptional corepressors that interact with the MEF2 transcription factors and the N-CoR, BCoR, and CtBP corepressors. Intriguingly, HDAC4, HDAC5, and probably HDAC7 are regulated through subcellular compartmentalization controlled by site-specific phosphorylation and binding of 14-3-3 proteins; the regulation of these HDACs is thus directly linked to cellular signaling networks. Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions. Comprehension of the structure, function, and regulation of class II deacetylases is important for elucidating how acetylation regulates functions of histones and other proteins in vivo.Key words: histone acetylation, protein acetylation, histone deacetylase, 14-3-3 proteins.

scholarly journals Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression

2000 ◽  
Vol 14 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Hung-Ying Kao ◽  
Michael Downes ◽  
Peter Ordentlich ◽  
Ronald M. Evans
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Class Ii ◽  
Class I ◽  
Nuclear Compartment ◽  
New Family ◽  
Repressive Effect ◽  
Two Hybrid

The transcriptional corepressor SMRT functions by mediating the repressive effect of transcription factors involved in diverse signaling pathways. The mechanism by which SMRT represses basal transcription has been proposed to involve the indirect recruitment of histone deacetylase HDAC1 via the adaptor mSin3A. In contrast to this model, a two-hybrid screen on SMRT-interacting proteins resulted in the isolation of the recently described HDAC5 and a new family member termed HDAC7. Molecular and biochemical results indicate that this interaction is direct and in vivo evidence colocalizes SMRT, mHDAC5, and mHDAC7 to a distinct nuclear compartment. Surprisingly, HDAC7 can interact with mSin3A in yeast and in mammalian cells, suggesting association of multiple repression complexes. Taken together, our results provide the first evidence that SMRT-mediated repression is promoted by class I and class II histone deacetylases and that SMRT can recruit class II histone deacetylases in a mSin3A-independent fashion.

scholarly journals Functional genetic encoding of sulfotyrosine in mammalian cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xinyuan He ◽  
Yan Chen ◽  
Daisy Guiza Beltran ◽  
Maia Kelly ◽  
Bin Ma ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Biochemical Characterization ◽  
Trna Synthetase ◽  
Functional Verification ◽  
Cellular Processes ◽  
Genetic Encoding ◽  
Efficient Expression

Abstract Protein tyrosine O-sulfation (PTS) plays a crucial role in extracellular biomolecular interactions that dictate various cellular processes. It also involves in the development of many human diseases. Regardless of recent progress, our current understanding of PTS is still in its infancy. To promote and facilitate relevant studies, a generally applicable method is needed to enable efficient expression of sulfoproteins with defined sulfation sites in live mammalian cells. Here we report the engineering, in vitro biochemical characterization, structural study, and in vivo functional verification of a tyrosyl-tRNA synthetase mutant for the genetic encoding of sulfotyrosine in mammalian cells. We further apply this chemical biology tool to cell-based studies on the role of a sulfation site in the activation of chemokine receptor CXCR4 by its ligand. Our work will not only facilitate cellular studies of PTS, but also paves the way for economical production of sulfated proteins as therapeutic agents in mammalian systems.

scholarly journals Phosphorylation of Serine 239 of Groucho/TLE1 by Protein Kinase CK2 Is Important for Inhibition of Neuronal Differentiation

2004 ◽  
Vol 24 (19) ◽  
pp. 8395-8407 ◽  
Author(s):  
Hugh N. Nuthall ◽  
Kerline Joachim ◽  
Stefano Stifani
Keyword(s):  
Protein Kinase ◽  
Neuronal Differentiation ◽  
Mammalian Cells ◽  
Protein Kinase Ck2 ◽  
Molecular Mechanisms ◽  
Transcription Repression ◽  
Transcriptional Corepressors ◽  
Kinase Ck2 ◽  
Nuclear Association

ABSTRACT Transcriptional corepressors of the Groucho (Gro)/TLE family play important roles during a variety of developmental pathways, including neuronal differentiation. In particular, they act as negative regulators of neurogenesis, together with Hairy/Enhancer of split (Hes) DNA-binding proteins. The interaction with Hes1 leads to Gro/TLE hyperphosphorylation and increased transcription repression activity in mammalian cells, but the underlying molecular mechanisms are poorly characterized. We now show that Gro/TLE1 is phosphorylated in vivo by protein kinase CK2. This phosphorylation occurs at serine 239 within the conserved CcN domain present in all Gro/TLE family members. Mutation of serine 239 into alanine decreases Hes1-induced hyperphosphorylation of Gro/TLE1 and also reduces its nuclear association and transcription repression activity. We demonstrate further that Gro/TLE1 inhibits the transition of cortical neural progenitors into neurons and that its antineurogenic activity is inhibited by a serine-239-alanine mutation but not by a serine-239-glutamate mutation. These results suggest that CK2 phosphorylation of serine 239 of Gro/TLE1 is important for its function during neuronal differentiation.

scholarly journals PP2A Regulates HDAC4 Nuclear Import

2008 ◽  
Vol 19 (2) ◽  
pp. 655-667 ◽  
Author(s):  
Gabriela Paroni ◽  
Nadia Cernotta ◽  
Claudio Dello Russo ◽  
Paola Gallinari ◽  
Michele Pallaoro ◽  
...  
Keyword(s):  
Nuclear Import ◽  
Nuclear Export ◽  
Histone Deacetylases ◽  
Phosphorylation Site ◽  
Class Ii ◽  
Binding Studies ◽  
Nuclear Entry ◽  
Putative Phosphorylation Site

Different signal-regulated serine/threonine kinases phosphorylate class II histone deacetylases (HDACs) to promote nuclear export, cytosolic accumulation, and activation of gene transcription. However, little is known about mechanisms operating in the opposite direction, which, possibly through phosphatases, should promote class II HDACs nuclear entry and subsequent gene repression. Here we show that HDAC4 forms a complex with the PP2A holoenzyme Cα, Aα, B/PR55α. In vitro and in vivo binding studies demonstrate that the N-terminus of HDAC4 interacts with the catalytic subunit of PP2A. HDAC4 is dephosphorylated by PP2A and experiments using okadaic acid or RNA interference have revealed that PP2A controls HDAC4 nuclear import. Moreover, we identified serine 298 as a putative phosphorylation site important for HDAC4 nuclear import. The HDAC4 mutant mimicking phosphorylation of serine 298 is defective in nuclear import. Mutation of serine 298 to alanine partially rescues the defect in HDAC4 nuclear import observed in cells with down-regulated PP2A. These observations suggest that PP2A, via the dephosphorylation of multiple serines including the 14-3-3 binding sites and serine 298, controls HDAC4 nuclear import.

scholarly journals INSM1 functions as a transcriptional repressor of the neuroD/β2 gene through the recruitment of cyclin D1 and histone deacetylases

2006 ◽  
Vol 397 (1) ◽  
pp. 169-177 ◽  
Author(s):  
Wei-Dong Liu ◽  
Hong-Wei Wang ◽  
Michelle Muguira ◽  
Mary B. Breslin ◽  
Michael S. Lan
Keyword(s):  
Cyclin D1 ◽  
Chromatin Immunoprecipitation ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Transcriptional Repressor ◽  
Chromatin Immunoprecipitation Assay ◽  
Immunoprecipitation Assay ◽  
Repressor Activity

INSM1/IA-1 (insulinoma-associated 1) is a developmentally regulated zinc-finger transcription factor, exclusively expressed in the foetal pancreas and nervous system, and in tumours of neuroendocrine origin. We have identified an INSM1 binding site in the neuroD/β2 promoter and demonstrated transcriptional repressor activity of INSM1 by transient transfection assay. A chromatin immunoprecipitation assay confirmed that in vivo INSM1 is situated on the promoter region of the neuroD/β2 gene. In an attempt to elucidate the molecular mechanism of transcriptional repression by the INSM1 gene, cyclin D1 was identified as an interacting protein by using a 45-day-old human foetal brain cDNA library and a yeast two-hybrid screen. The physical association between INSM1 and cyclin D1 was confirmed by in vitro and in vivo pull-down assay. Cyclin D1 co-operates with INSM1 and suppresses neuroD/β2 promoter activity. Co-immunoprecipitation of INSM1, cyclin D1 and HDACs (histone deacetylases) in mammalian cells revealed that INSM1 interacts with HDAC-1 and -3 and that this interaction is mediated through cyclin D1. Overexpression of cyclin D1 and HDAC-3 significantly enhanced the transcriptional repression activity of INSM1 on the neuroD/β2 promoter. A further chromatin immunoprecipitation assay confirmed that HDAC-3 occupies this same region of the neuroD/β2 promoter, by forming a transcription complex with INSM1. Thus we conclude that INSM1 recruits cyclin D1 and HDACs, which confer transcriptional repressor activity.

scholarly journals Versatile Role for hnRNP D Isoforms in the Differential Regulation of Cytoplasmic mRNA Turnover

2001 ◽  
Vol 21 (20) ◽  
pp. 6960-6971 ◽  
Author(s):  
Nianhua Xu ◽  
Chyi-Ying A. Chen ◽  
Ann-Bin Shyu
Keyword(s):  
Mammalian Cells ◽  
Mrna Decay ◽  
Sequence Similarity ◽  
Class Ii ◽  
Negative Regulator ◽  
Mrna Turnover ◽  
Dependent Manner ◽  
Coding Region ◽  
Hnrnp D

ABSTRACT An important emerging theme is that heterogeneous nuclear ribonucleoproteins (hnRNPs) not only function in the nucleus but also control the fates of mRNAs in the cytoplasm. Here, we show that hnRNP D plays a versatile role in cytoplasmic mRNA turnover by functioning as a negative regulator in an isoform-specific and cell-type-dependent manner. We found that hnRNP D discriminates among the three classes of AU-rich elements (AREs), most effectively blocking rapid decay directed by class II AREs found in mRNAs encoding cytokines. Our experiments identified the overlapping AUUUA motifs, one critical characteristic of class II AREs, to be the key feature recognized in vivo by hnRNP D for its negative effect on ARE-mediated mRNA decay. The four hnRNP D isoforms, while differing in their ability to block decay of ARE-containing mRNAs, all potently inhibited mRNA decay directed by another mRNA cis element that shares no sequence similarity with AREs, the purine-rich c-fosprotein-coding region determinant of instability. Further experiments indicated that different mechanisms underlie the inhibitory effect of hnRNP D on the two distinct mRNA decay pathways. Our study identifies a potential mechanism by which cytoplasmic mRNA turnover can be differentially and selectively regulated by hnRNP D isoforms in mammalian cells. Our results support the notion that hnRNP D serves as a key factor broadly involved in general mRNA decay.

scholarly journals Inhibition of Polyomavirus ori-Dependent DNA Replication by mSin3B

2002 ◽  
Vol 76 (23) ◽  
pp. 11809-11818 ◽  
Author(s):  
An-Yong Xie ◽  
William R. Folk
Keyword(s):  
Dna Replication ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class Ii ◽  
T Antigen ◽  
Class I ◽  
Large T Antigen ◽  
Transcriptional Corepressor ◽  
Independent Mechanism

ABSTRACT When tethered in cis to DNA, the transcriptional corepressor mSin3B inhibits polyomavirus (Py) ori-dependent DNA replication in vivo. Histone deacetylases (HDACs) appear not to be involved, since tethering class I and class II HDACs in cis does not inhibit replication and treating the cells with trichostatin A does not specifically relieve inhibition by mSin3B. However, the mSin3B L59P mutation that impairs mSin3B interaction with N-CoR/SMRT abrogates inhibition of replication, suggesting the involvement of N-CoR/SMRT. Py large T antigen interacts with mSin3B, suggesting an HDAC-independent mechanism by which mSin3B inhibits DNA replication.

scholarly journals Evaluation in mammalian oocytes of gene transcripts linked to epigenetic reprogramming

Reproduction ◽  
2007 ◽  
Vol 134 (4) ◽  
pp. 549-558 ◽  
Author(s):  
Roberto S Oliveri ◽  
Mark Kalisz ◽  
Charlotte Karlskov Schjerling ◽  
Claus Yding Andersen ◽  
Rehannah Borup ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Dna Methyltransferase ◽  
Germinal Vesicle ◽  
Epigenetic Reprogramming ◽  
Sperm Chromatin ◽  
Somatic Nucleus ◽  
Covalent Modifications

The mature mammalian metaphase II (MII) oocyte has a unique ability to reprogram sperm chromatin and support early embryonic development. This feature even extends to the epigenetic reprogramming of a terminally differentiated cell nucleus as observed in connection with somatic cell nuclear transfer. Epigenetic nuclear reprogramming is highly linked to chromatin structure and includes covalent modifications of DNA and core histone proteins as well as reorganization of higher-order chromatin structure. A group of conserved enzymes mediating DNA methylation, methyl-CpG-binding protein (MeCP), histone acetylation and methylation, and chromatin remodeling are extensively involved in epigenetic reprogramming in mammalian cells. Using the oligonucleotide microarray technique, the present study compared the expression levels of 86 genes associated with epigenetic reprogramming in murine in vivo matured MII oocytes with that of germinal vesicle oocytes. Correlation between biological replicates was high. A total of 57 genes with potential reprogramming effect were detected. In MII oocytes, four genes were significant up-regulated, whereas 18 were down-regulated and 35 unchanged. The significantly regulated genes were validated by real-time quantitative RT-PCR. For example, MII oocytes showed a significant down-regulation of oocyte-specific maintenance DNA methyltransferase, Dnmt1o, and up-regulation of MeCP transcript, methyl-CpG binding domain protein 2. Furthermore, histone acetyltransferases were proportionally overrepresented when compared with histone deacetylases. These data elucidate for the first time some of the mechanisms that the oocyte may employ to reprogram a foreign genome either in form of a spermatozoa or a somatic nucleus and may thus be of importance for advancing the fields of stem cell research and regenerative medicine.

scholarly journals Mammalian synthetic biology for studying the cell

2016 ◽  
Vol 216 (1) ◽  
pp. 73-82 ◽  
Author(s):  
Melina Mathur ◽  
Joy S. Xiang ◽  
Christina D. Smolke
Keyword(s):  
Synthetic Biology ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Regulatory Networks ◽  
Dynamic Control ◽  
Model Systems ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Regulatory Processes ◽  
Multicellular Interactions

Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology.

scholarly journals Novel Inhibitor of Plasmodium Histone Deacetylase That Cures P. berghei-Infected Mice

2009 ◽  
Vol 53 (5) ◽  
pp. 1727-1734 ◽  
Author(s):  
S. Agbor-Enoh ◽  
C. Seudieu ◽  
E. Davidson ◽  
A. Dritschilo ◽  
M. Jung
Keyword(s):  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Hdac Inhibitors ◽  
High Drug ◽  
Lead Compounds ◽  
Drug Concentrations

ABSTRACT Histone deacetylases (HDAC) are potential targets for the development of new antimalarial drugs. The growth of Plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent HDAC inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. Furthermore, most established HDAC inhibitors concurrently show broad toxicities against parasites and human cells and high drug concentrations are required for effective antimalarial activity. Here, we report on HDAC inhibitors that are potent against P. falciparum at subnanomolar concentrations and that have high selectivities; the lead compounds have mean 50% inhibitory concentrations for the killing of the malaria parasite up to 950 times lower than those for the killing of mammalian cells. These potential drugs improved survival and completely and irreversibly suppressed parasitemia in P. berghei-infected mice.

Sign in / Sign up

Export Citation Format

Share Document